Multilevel Barriers to the Successful Implementation of Lung Cancer Screening: Why Does It Have to Be So Hard?
The U.S. Preventive Services Task Force recommends lung cancer screening with low-dose computed tomography for long-term current and former smokers. However, lung cancer screening and its implementation are a complex issue. Screening has associated risks and potential harms that complicate the decision to screen for the patient, add to the already time-constrained clinical encounter for the provider, and present logistical and sociopolitical challenges in creating and implementing lung cancer screening programs in the health care system. As lung cancer screening is more widely implemented in the United States, it is critical for those in the health care system to be cognizant of potential barriers to effective screening implementation at the patient, provider, and system levels when designing effective support interventions, as well as to proactively address potential impediments to this new screening option. This paper presents perspectives on these multilevel barriers to lung cancer screening.


Temporal Dynamics of Human Frontal and Cingulate Neural Activity During Conflict and Cognitive Control.
Cognitive control refers to the ability to produce flexible, goal-oriented behavior in the face of changing task demands and conflicting response tendencies. A classic cognitive control experiment is the Stroop-color naming task, which requires participants to name the color in which a word is written while inhibiting the tendency to read the word. By comparing stimuli with conflicting word-color associations to congruent ones, control processes over response tendencies can be isolated. We assessed the spatial specificity and temporal dynamics in the theta and gamma bands for regions engaged in detecting and resolving conflict in a cohort of 13 patients using a combination of high-resolution surface and depth recordings. We show that cognitive control manifests as a sustained increase in gamma band power, which correlates with response time. Conflict elicits a sustained gamma power increase but a transient theta power increase, specifically localized to the left cingulate sulcus and bilateral dorsolateral prefrontal cortex (DLPFC). Additionally, activity in DLPFC is affected by trial-by-trial modulation of cognitive control (the Gratton effect). Altogether, the sustained local neural activity in dorsolateral and medial regions is what determines the timing of the correct response.


Organization and work of the war hospital in Tomislavgrad during the war in Bosnia and Herzegovina from 1992 to 1995.
The work of the War Hospital in Tomislavgrad during the war in Bosnia and Herzegovina from 1992 to 1995 is described. The War Hospital in Tomislavgrad was one of the first medical institutions organized in Bosnia and Herzegovina, with the intention of providing surgical treatment and care to soldiers, local civilians, and refugees who found shelter in this part of the country. It was located on the main communication route connecting Bosnia and Herzegovina and the south part of Croatia. During the 4-year period, 23,191 examinations, of which 8,341 were first-time examinations, and 1,547 surgical operations were performed. The hospital provided a high level of surgical and anesthesiology service in an area where none existed before the war. All patients were treated regardless of their nationality or religion, thus mitigating the consequences of the war.


Identification and molecular characterization of the calmodulin-binding subunit gene (CMP1) of protein phosphatase 2B from Saccharomyces cerevisiae. An alpha-factor inducible gene.
A method has been developed for the rapid purification of yeast calmodulin in high yield. Using a 125I-labeled calmodulin SDS/PAGE gel overlay procedure with either yeast or bovine calmodulin, we show that the bovine and yeast proteins recognize the same proteins in total yeast extracts. However, yeast calmodulin does not bind to many of the proteins in vertebrate cells identified using bovine calmodulin. A lambda gt11 yeast genomic expression library was screened with yeast or bovine brain 125I-calmodulin to identify sequences derived from calmodulin binding proteins. Twelve clones were recovered, all containing a common DNA insert; all bound calmodulin in a Ca(2+)-dependent manner. The complete coding sequence was recovered and sequenced. The predicted protein sequence show greater than 50% identity to the A subunit of vertebrate protein phosphatase 2B. The gene was designated CMP1 and shown to reside on chromosome IV. Disruption or over-expression of CMP1 have no obvious phenotype; yeast appears to contain one or more CMP1-related genes. The protein product of the CMP1 gene is elevated by alpha-factor treatment, suggesting an involvement of protein phosphatase 2B in the mating response.


Alloimmune hemolytic disease of the fetus and newborn: genetics, structure, and function of the commonly involved erythrocyte antigens.
Hemolytic disease of the fetus and newborn (HDFN) can occur when a pregnant woman has antibody directed against an erythrocyte surface antigen expressed by her fetus. This alloimmune disorder is restricted to situations where transplacental transfer of maternal antibody to the fetus occurs, and binds to fetal erythrocytes, and significantly shortens the red cell lifespan. The pathogenesis of HDFN involves maternal sensitization to erythrocyte "non-self" antigens (those she does not express). Exposure of a woman to a non-self-erythrocyte antigen principally occurs through either a blood transfusion or a pregnancy where paternally derived erythrocyte antigens, expressed by her fetus, enter her circulation, and are immunologically recognized as foreign. This review focuses on the genetics, structure, and function of the erythrocyte antigens that are most frequently involved in the pathogenesis of alloimmune HDFN. By providing this information we aim to convey useful insights to clinicians caring for patients with this condition.


Nucleotide sequence of the pyruvate decarboxylase gene from Zymomonas mobilis.
Pyruvate decarboxylase (EC 22.214.171.124), the penultimate enzyme in the alcoholic fermentation pathway of Zymomonas mobilis, converts pyruvate to acetaldehyde and carbon dioxide. The complete nucleotide sequence of the structural gene encoding pyruvate decarboxylase from Zymomonas mobilis has been determined. The coding region is 1704 nucleotides long and encodes a polypeptide of 567 amino acids with a calculated subunit mass of 60,790 daltons. The amino acid sequence was confirmed by comparison with the amino acid sequence of a selection of tryptic fragments of the enzyme. The amino acid composition obtained from the nucleotide sequence is in good agreement with that obtained experimentally.


Fine structure of the mineralized teeth of the chiton Acanthopleura echinata (Mollusca: Polyplacophora).
The major lateral teeth of the chiton Acanthopleura echinata are composite structures composed of three distinct mineral zones: a posterior layer of magnetite; a thin band of lepidocrocite just anterior to this; and apatite throughout the core and anterior regions of the cusp. Biomineralization in these teeth is a matrix-mediated process, in which the minerals are deposited around fibers, with the different biominerals described as occupying architecturally discrete compartments. In this study, a range of scanning electron microscopes was utilized to undertake a detailed in situ investigation of the fine structure of the major lateral teeth. The arrangement of the organic and biomineral components of the tooth is similar throughout the three zones, having no discrete borders between them, and with crystallites of each mineral phase extending into the adjacent mineral zone. Along the posterior surface of the tooth, the organic fibers are arranged in a series of fine parallel lines, but just within the periphery their appearance takes on a "fish scale"-like pattern, reflective of the cross section of a series of units that are overlaid, and offset from each other, in adjacent rows. The units are approximately 2 microm wide and 0.6 microm thick and comprise biomineral plates separated by organic fibers. Two types of subunits make up each "fish scale": one is elongate and curved and forms a trough, in which the other, rod-like unit, is nestled. Adjacent rod and trough units are aligned into large sheets that define the fracture plane of the tooth. The alignment of the plates of rod-trough units is complex and exhibits extreme spatial variation within the tooth cusp. Close to the posterior surface the plates are essentially horizontal and lie in a lateromedial plane, while anteriorly they are almost vertical and lie in the posteroanterior plane. An understanding of the fine structure of the mineralized teeth of chitons, and of the relationship between the organic and mineral components, provides a new insight into biomineralization mechanisms and controls.


Topic and Content of Personal Narratives of Children from Three East Asian Cultures and Three English-Speaking Cultures: A Collaborative Qualitative Analysis.
Narrative language skills are critical for effective social interactions and academic success. Consequently, narratives are regularly an aspect of assessment and intervention for children with communication impairments, supporting the need for information about typical development from children across cultures. Development of coherent personal narratives is associated with growth of both one's individual identity and cultural identity which are linked to psychological well-being. The topics and contents of children's personal stories can provide insight into cultural influences on what children consider important, how they interpret experiences, and their values and beliefs, which in turn contribute to their developing individual and cultural self-identity. The purpose of this study was to investigate the topics and content of personal narratives told by typically developing 10-year-old children from East Asian and Western English-speaking cultures. There were 20 children in each of three East Asian language groups - Mandarin, Cantonese, and Korean; and 62 children in the English-speaking groups (22 in the USA and 20 each in the Australian and New Zealand groups). In each group, half were boys and half were girls. Children responded to prompts from the Global TALES protocol to elicit personal narratives. All language samples were transcribed, translated, and coded for topic choices using qualitative content analysis in collaborative discussions by the four authors, who included an English-speaking author from the USA (C.E.W.), and three authors, who are native speakers of the three East Asian languages, Mandarin (K.-M.C.), Cantonese (A.M.-Y.W.), and Korean (J.P.L.). Results on topics in stories from East Asian and Western English-speaking cultures are described in relation to literature on anthropology. English-speaking children and East Asian children in this study talked about similar topics in their personal narratives, but the frequency of these topics within their stories varied. Possible explanations for differences in story topics are discussed within a framework on cultural dimensions. Evaluation of the topics of children's personal narratives provides insight into what is important to the children and the way they view their worlds. This information may inform clinical approaches to assessment and intervention with children with communication impairments, encouraging clinicians to go beyond analysis of language structure to consider multiple factors that influence communicative competence.


Virulence factors in Escherichia coli with CTX-M-15 and other extended-spectrum beta-lactamases in the UK.
Multiresistant Escherichia coli with CTX-M-15 extended-spectrum beta-lactamase (ESBL) are widespread in the UK. We examined their phylogenetic groups and virulence factors. Clinical E. coli isolates (n = 114), collected between 2003 and 2006, were phylogenetically grouped and screened by PCR for 33 virulence factor genes. They included representatives of the five major UK epidemic E. coli strains with CTX-M-15 enzyme, as well as non-clonal isolates with CTX-M or other types of ESBLs. All representatives of the epidemic E. coli strains belonged to the virulent extra-intestinal phylogenetic group B2, as did 60% (34/56) of the non-clonal isolates with CTX-M-15-like enzymes and 75% (15/20) of those with non-CTX-M ESBLs. Half of those with CTX-M-9-like enzymes belonged to virulence group D. Within phylogenetic group B2, the prevalence of most virulence factors was comparable among clonal and non-clonal isolates with CTX-M enzymes, and among those with non-CTX-M ESBLs. The most frequent virulence genes were PAI, fimH, fyuA, iutA, kpsMTII, K5, traT, uidA and usp. Among the five epidemic clones, afa/draBC was specific to strain A, whereas P fimbriae were only detected in strain D, and only representatives of the B-C-E group specifically harboured sfaS, kpsMTII and K5. However, afa/draBC was also found in 30% of non-clonal isolates with CTX-M ESBLs, and no virulence gene was unique to the epidemic strains. Most E. coli with CTX-M ESBLs belonged to virulent phylogenetic groups, mainly B2. The successful epidemic strains did not appear more virulent, but iutA and fyuA were significantly more prevalent among these than in non-clonal isolates also belonging to phylogenetic group B2. The most successful clone with CTX-M-15 enzyme (A) differed from other epidemic clones in harbouring afa/draBC, but this was also found in non-clonal isolates with CTX-M-15 enzyme.


Long-term clearance of liquid and protein from the lungs of unanesthetized sheep.
We measured the removal of 100 ml of autologous serum from the air spaces and lungs of unanesthetized, spontaneously breathing sheep at 4, 12, and 24 h. In the first 4 h, there was a rapid clearance of the liquid volume (8.3%/h), similar to our results in anesthetized ventilated sheep (Matthay et al., J. Appl. Physiol. 53: 96-104, 1982). However, liquid removal progressively slowed to 3.3 and 1.4%/h at 12 and 24 h, respectively. In contrast, protein clearance (as measured by 125I-albumin instilled with the serum) was monoexponential and slow (1%/h). The slowing of liquid clearance appears to be a function of the rising protein osmotic pressure of the residual protein in the air spaces (protein concentration doubled in 24 h). Because protein solutions are chemotactic for neutrophils, we quantified the movement of liquid from the extracellular space into the alveolar compartment with a plasma protein tracer (131I-albumin), so that our final calculation of alveolar liquid clearance would take into account bidirectional movement of liquid across the alveolar barrier. The corrected values for net liquid clearance are slightly faster (less than 10% of the instilled volume).


Quantitative and qualitative analysis of heart mitochondria for evaluating the degree of myocardial injury utilizing atomic force microscopy.
Mitochondrial dysfunction plays a central role in mediating both the necrotic and apoptotic components of reperfusion injury. Because mitochondrial swelling is one of the most important indicators of the beginning of mitochondrial permeability transition, quantification of morphological changes in mitochondria would be useful in evaluating the degree of IR injury, as well as the protective effects of various therapies. In this study, we characterized the morphological changes in heart mitochondria caused by the duration and severity of ischemia utilizing particle shape analysis on atomic force microscopy (AFM) topographic images. We also simultaneously investigated the nano-mechanical changes in rat heart mitochondria by injury using force-distance curve measurements. Rats were randomly divided into 3 groups: control group (n=3), myocardial ischemia without reperfusion (PI group, n=3), and myocardial ischemia with reperfusion (IR group, n=4). Normal mitochondria appeared ellipsoidal with a mean area of 3551±1559 nm(2) and mean perimeter of 217.54±52.09 nm (n=60). The mean area and perimeter of mitochondria in the IR groups increased to 28,181±21,248 nm(2) and 595.74±234.29 nm (n=40, p<0.0001 vs. control group, respectively), maintaining oval in shape. But, in the PI group, all parameters showed significant differences compared to parameters of the control group (n=35, p<0.0001). In particular, the mean axial ratio and roundness were significantly different from those in the IR group. Mitochondria in the PI group looked more spherical than those of control and IR groups. Adhesion force is the force before the last event on the retraction half of force-distance curve measurements, corresponding to the point where the tip and the surface loose contact. The adhesion forces of heart mitochondria in the IR and PI groups significantly decreased to 19.56±1.08 nN (n=30, p<0.0001) and 18.65±3.18 nN (n=30, p<0.0001), compared to normal mitochondria which had an adhesion force of 27.64±0.88 nN (n=30). Adhesion force is governed by the attractive portion of the interacting forces between the surface atoms of the contacts. From the morphological and nano-mechanical changes in heart mitochondria, we suggested that the outer membranes of mitochondria were broken by myocardial ischemic injury before they became swollen, and the swelling might be correlated with the ischemic injury. We inferred that the breakage of membranes leads to uptake of water and matrix swelling. As a result, shape measurement parameters for the quantitative analysis of mitochondrial swelling could be very effective for evaluating the myocardial injury.


The effect of mechanical stress on enthesis homeostasis in a rat Achilles enthesis organ culture model.
Tendons and ligaments are jointed to bones via an enthesis that is essential to the proper function of the muscular and skeletal structures. The aim of the study is to investigate the effect of mechanical stress on the enthesis. We used ex vivo models in organ cultures of rat Achilles tendons with calcaneus including the enthesis. The organ was attached to a mechanical stretching apparatus that can conduct cyclic tensile strain. We made the models of 1-mm elongation (0.5 Hz, 3% elongation), 2-mm elongation (0.5 Hz, 5% elongation), and no stress. Histological evaluation by Safranin O staining and Toluidin Blue and Picro Sirius red staining was conducted. Expression of sex-determining region Y-box 9 (Sox9), scleraxis (Scx), Runt-related transcription factor 2 (Runx2), and matrix metalloproteinase 13 (Mmp13) were examined by real-time polymerase chain reaction and immunocytochemistry. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling and live/dead staining and was conducted for evaluation of the apoptosis and cell viability. The structure of the enthesis was most maintained in the model of 1-mm elongation. The electronic microscope showed that the enthesis of the no stress model had ill-defined borders between fibrocartilage and mineralized fibrocartilage, and that calcification of mineralized fibrocartilage occurred in the model of 2-mm elongation. Sox9 and Scx was upregulated by 1-mm elongation, whereas Runx2 and Mmp13 were upregulated by 2-mm elongation. Apoptosis was inhibited by low stress. The results of this study suggested that 1-mm elongation can maintain the structure of the enthesis, while 2-mm elongation promotes degenerative changes.


Survey on Antimicrobial Drug Use Practices in California Preweaned Dairy Calves.
The California (CA) dairy industry was surveyed in July 2017 to evaluate producers' knowledge and perceptions and antimicrobial drug (AMD) use in preweaned dairy calves following the implementation of the nationwide veterinary feed directive final rule (VFD) in January 2017 and prior to statewide implementation of CA Senate Bill (SB) 27 in January 2018. Together, these regulations require veterinary oversight for all uses of medically important antimicrobial drugs (MIADs) administered to livestock in CA. Survey questionnaire was mailed to 1,361 CA Grade A milk producing dairies and calf ranches across CA resulting in a 12% (169) response. Most respondents (83%) were aware of the VFD and SB 27 changes. Use of antibiotics was perceived as important (77%) in raising preweaned dairy calves and judicious use of antibiotics was ranked as the most important antimicrobial stewardship practice, amongst record keeping, observing withdrawal periods, having a valid Veterinarian-Client-Patient-Relationship (VCPR), and use of alternatives to antibiotics. Treating sick calves was the major indication for AMD use (90.5%); however, few producers reported use of antibiotics to control (12.7%) or prevent disease (11%). Neomycin sulfate, chlortetracycline, oxytetracycline and sulfamethazine were the most used AMD. The respondents reported a decreased use of AMD in milk (10%) and in solid feed (5%), and discontinuation of one or more AMDs used in milk (18.6%) or in solid feed (5%) post-VFD rule implementation in 2017. Most respondents reported keeping treatment records and the information recorded included date (82%), dose (44%) and route (15%) of AMD used. A few respondents reported they had initiated use of alternatives to AMDs, such as vitamins (32.6%), minerals (25.6%), herbal remedies (11.6%) and pathogen specific antibodies (7%), post-VFD. The limited changes noted in AMD use could be attributed to the short period between the implementation of the VFD and the time of the survey. Our study outcomes identified opportunities to improve AMD use practices, including record keeping and use of AMD alternatives, and provides a baseline for future evaluation of the impact of these regulatory changes, as well as guidance for the future recommendations on best practices to promote judicious AMD use.


A Randomized Comparison Between Conventional and Waveform-Confirmed Loss of Resistance for Thoracic Epidural Blocks.
Epidural waveform analysis (EWA) provides a simple confirmatory adjunct for loss of resistance (LOR): when the needle tip is correctly positioned inside the epidural space, pressure measurement results in a pulsatile waveform. In this randomized trial, we compared conventional and EWA-confirmed LOR in 2 teaching centers. Our research hypothesis was that EWA-confirmed LOR would decrease the failure rate of thoracic epidural blocks. One hundred patients undergoing thoracic epidural blocks for thoracic surgery, abdominal surgery, or rib fractures were randomized to conventional LOR or EWA-LOR. The operator was allowed as many attempts as necessary to achieve a satisfactory LOR (by feel) in the conventional group. In the EWA-LOR group, LOR was confirmed by connecting the epidural needle to a pressure transducer using a rigid extension tubing. Positive waveforms indicated that the needle tip was positioned inside the epidural space. The operator was allowed a maximum of 3 different intervertebral levels to obtain a positive waveform. If waveforms were still absent at the third level, the operator simply accepted LOR as the technical end point. However, the patient was retained in the EWA-LOR group (intent-to-treat analysis).After achieving a satisfactory tactile LOR (conventional group), positive waveforms (EWA-LOR group), or a third intervertebral level with LOR but no waveform (EWA-LOR group), the operator administered a 4-mL test dose of lidocaine 2% with epinephrine 5 μg/mL. Fifteen minutes after the test dose, a blinded investigator assessed the patient for sensory block to ice. Compared with LOR, EWA-LOR resulted in a lower rate of primary failure (2% vs 24%; P = 0.002). Subgroup analysis based on experience level reveals that EWA-LOR outperformed conventional LOR for novice (P = 0.001) but not expert operators. The performance time was longer in the EWA-LOR group (11.2 ± 6.2 vs 8.0 ± 4.6 minutes; P = 0.006). Both groups were comparable in terms of operator's level of expertise, depth of the epidural space, approach, and LOR medium. In the EWA-LOR group, operators obtained a pulsatile waveform with the first level attempted in 60% of patients. However, 40% of subjects required performance at a second or third level. Compared with its conventional counterpart, EWA-confirmed LOR results in a lower failure rate for thoracic epidural blocks (2% vs 24%) in our teaching centers. Confirmatory EWA provides significant benefits for inexperienced operators.


Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes. Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed. Sixty-two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy. Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available.


Localization of FMRFamide-like peptides in the snail Helix aspersa.
The distribution of FMRFamide-like material in the gastropod mollusc, Helix aspersa, was studied by radioimmunoassay (RIA) and immunocytochemistry. Most of the RIA activity was concentrated in the central nervous system, the male reproductive tract, the tentacles and the posterior digestive system (Table 1). The density of FMRFamidergic perikarya, nerves and nerve varicosities in the muscle tissue of all these regions, as indicated immunocytochemically (Fig. 2), was well correlated with the distribution as determined by RIA. Gel chromatography of each extract resolved two peaks of FMRFamide-like immunoreactivity (Fig. 3). The first of these was further analysed by high-pressure liquid chromatography (HPLC), and the components included two major immunoreactive peaks identifiable, both by their retention times and their effects on the radula protractor muscle of Busycon contrarium, as the known peptides FMRFamide and pQDPFLRFamide (Figs 4-6). The second peak from gel chromatography gave only a single peak, distinct from that of FMRFamide and pQDPFLRFamide, in two HPLC systems (Fig. 7), but it did not behave like a competitive ligand in the FMRFamide RIA. Moreover, its immunoreactivity, unlike any peptides we tested, was not affected by carboxypeptidase Y (Fig. 8), and it was not active on the radula protractor muscle. Thus, it is certainly not an FMRFamide-like peptide. We conclude that Helix aspersa contains at least two FMRFamide-like peptides, FMRFamide and pQDPFLRFamide. These peptides appear to act both as neurohormones and as neurotransmitters or modulators in the central ganglia, reproductive, digestive, muscular and circulatory systems.


Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.
Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.


Surgical results of retroauricular fascia graft in frontalis suspension surgery: A case series study.
Frontalis suspension surgery is commonly used for the repair of congenital ptosis and involutional blepharoptosis with poor levator function. Grafts for this procedure have been developed using a variety of different materials, each with advantages and disadvantages. The retroauricular fascia graft might be beneficial in this surgery. This article reports the surgical results of blepharoptosis, who were treated with the retroauricular fascia, which is a new autologous graft for the frontalis suspension technique. This case series study targeted patients with ptosis who underwent frontalis suspension surgery with the retroauricular fascia graft at Wakayama Medical University in Japan between May 2016 and May 2023. Patients with insufficient follow-up (<6 months) were excluded from the study. Eligible patients were categorized into one of the following three assessment groups: "good" (improvement of palpebral fissure height without laterality, Margin reflex distance-1 gap between right and left side <0.5 mm), "fair" (improvement of palpebral fissure height with laterality), or "poor" (poor improvement of palpebral fissure height). Thirty-five eyes in 25 patients were treated with the retroauricular fascia graft. The mean postoperative follow-up was 27 months. Eight patients were classified as good (32%), 15 as fair (60%), and two as poor (8%). Two patients (8%) had postoperative lagophthalmos. No patients had eyelash inversion, tarsal deformity, or recurrence of ptosis. Scars along the edge of the hairline were inconspicuous and there were no hypertrophic scars. Functional reconstruction of the eyelids using the retroauricular fascia graft technique is described here for the first time. This grafting technique may be a useful alternative for frontalis suspension surgery because it can be harvested with easy access and without leaving conspicuous scars.


On the potential of hyperpolarized water in biomolecular NMR studies.
A main obstacle arising when using ex situ hyperpolarization to increase the sensitivity of biomolecular NMR is the fast relaxation that macromolecular spins undergo upon being transferred from the polarizer to the spectrometer, where their observation takes place. To cope with this limitation, the present study explores the use of hyperpolarized water as a means to enhance the sensitivity of nuclei in biomolecules. Methods to achieve proton polarizations in excess of 5% in water transferred into the NMR spectrometer were devised, as were methods enabling this polarization to last for up to 30 s. Upon dissolving amino acids and polypeptides sited at the spectrometer into such hyperpolarized water, a substantial enhancement of certain biomolecular amide and amine proton resonances was observed. This exchange-driven (1)H enhancement was further passed on to side-chain and to backbone nitrogens, owing to spontaneous one-bond Overhauser processes. (15)N signal enhancements >500 over 11.7 T thermal counterparts could thus be imparted in a kinetic process that enabled multiscan signal averaging. Besides potential bioanalytical uses, this approach opens interesting possibilities in the monitoring of dynamic biomolecular processes, including solvent accessibility and exchange process.


Outcome measures for holistic, complex interventions within the palliative care setting.
As members of the Association of Palliative Care CAM (complementary and alternative medicine) Task Group we set ourselves two tasks: the task of exploring different facets of holistic care relevant to the palliative care setting and then to review outcome measures that might assist in researching complex interventions such as complementary therapies. Complementary therapies often embrace holistic philosophy where mind and body are connected and the complexity of symptoms acknowledged. These holistic or complex interventions within the palliative care setting are important to research and research holistically. We therefore gathered together outcome measures in the areas of hope, spirituality, symptom control, self-concept, the therapeutic consultation and dignity which would assist in the design of clinical trials of complementary therapies in the palliative care setting.


Evolution of Epigenetic Regulation in Vertebrate Genomes.
Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single-cell eukaryotes to human, comparative analyses are still relatively few and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. We review here the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site (TFBS) turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.


Isolation and immunological characterization of the nucleocapsid and membrane proteins of measles virus.
Measles virus nucleoprotein (NP) and matrix (M) components were purified by two different procedures. Antigens were prepared by sedimenting material from 1% Cutscum extracts of infected cells into the interphase between 65 and 40% sucrose and further fractionation of the interphase material in a linear CsCl gradient, density range 1.20 to 1.33 g/ml. NP components contaminated with some M material and cellular actin banded at 1.30 to 1.32 g/ml, but at the low density range of 1.20 to 1.22 g/ml pure M component was demonstrable. Partially denatured antigens were obtained by elution of the 60K NP and 36K M polypeptides after SDS-polyacrylamide slab gel electrophoresis. Rabbit hyperimmune sera were prepared against both purified antigens and isolated polypeptides. All sera reacted only with homologous antigen except the antiserum against NP components isolated from CsCl gradients, which also contained antibodies to the M component. Antibodies against NP antigen stained both intranuclear inclusions and cytoplasmic material in immune fluorescence tests. In contrast, antisera against M antigen only stained the cytoplasm. Since intranuclear nucleocapsids are smooth, whereas intracytoplasmic nucleocapsids are 'fuzzy', this may infer that the fuzziness, at least in part, is caused by M antigen adhering to nucleocapsid components.


Antioxidant function of ambroxol in mononuclear and polymorphonuclear cells in vitro.
This study quantifies the antioxidant function of ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine) in vitro. Polymorphonuclear cells (PMN) and mononuclear cells were isolated from the blood of healthy volunteers (n = 46) to determine reactive oxygen species (ROS) by luminol-enhanced chemiluminescence. Ambroxol or the controls N-acetylcysteine (NAC), nacystelyn (NAL), glutathione (GSH), superoxide dismutase (SOD), catalase, and the combination of SOD/catalase were incubated for 1 or 2 h with zymosan-activated cells in vitro using concentrations ranging from 10(-6) to 10(-3) mol/liter. Reduction of ROS-mediated luminescence was similar within the cell types. Ambroxol (10(-4) mol/liter) reduced ROS about 75% (1-h incubation) and 98% (2-h incubation), respectively (p < 0.001). SOD and SOD/catalase, but not the H2O2-catalyzing substances (NAC, NAL, GSH, and catalase), reduced cellular ROS. This indicates that inflammatory cells predominantly generate O2-, which can be scavenged by ambroxol. The antioxidant function of ambroxol with increasing incubation time suggests additional cellular antiinflammatory properties of this substance. Our results indicate that good antioxidant function of ambroxol is related mainly to direct scavenger function of reactive oxygen metabolites such as O2-. However, an antioxidative effect of ambroxol may also be associated with the reduction of prooxidative metabolism in inflammatory cells. Concluding from this observation, and because of the well known high affinity of ambroxol for lung tissue, ambroxol may be an alternative in antioxidant augmentation therapy, particularly in pulmonary diseases characterized by an overburden of toxic oxygen metabolites.


In vivo DNA damaging and apoptotic potential of silver nanoparticles in Swiss albino mice.
Nanoparticles can potentially cause adverse effects on organs, tissue, cell levels, and protein levels because of their physicochemical properties. Silver nanoparticles (AgNPs) are being used on a wide scale in world consumer markets; their potential hazards for humans remain largely unknown. This study aimed to investigate the intraperitoneal toxicity of AgNPs (26 mg per kg of body weight, 52 mg per kg of body weight, and 78 mg per kg of body weight) over 72 hours in Swiss albino mice. AgNPs induced a significant increase in serum liver injury markers including alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase. Induction of DNA damage was also studied in mice injected with AgNPs. Apoptosis (detected by using the terminal deoxynucleotidyl transferase deoxyuridine triphosphatase nick end labeling assay method) in liver tissue and DNA strand breaks (detected by using the comet assay method) in lymphocytes revealed that a concentration of 78 mg of AgNPs per kg body weight can cause significant apoptosis and DNA damage. The DNA damage and apoptosis raise the concern about the safety associated with application of the AgNPs. Significantly more alterations were induced in the hepatocytes of animals exposed to AgNP doses than in the control animals. The induced histological and apoptotic changes may be due to AgNP toxicity. Immunohistochemical and ultrastructural of AgNP.


Ideas, actors and institutions: lessons from South Australian Health in All Policies on what encourages other sectors' involvement.
This paper examines the extent to which actors from sectors other than health engaged with the South Australian Health in All Policies (HiAP) initiative, determines why they were prepared to do so and explains the mechanisms by which successful engagement happened. This examination applies theories of policy development and implementation. The paper draws on a five year study of the implementation of HiAP comprising document analysis, a log of key events, detailed interviews with 64 policy actors and two surveys of public servants. The findings are analysed within an institutional policy analysis framework and examine the extent to which ideas, institutional factors and actor agency influenced the willingness of actors from other sectors to work with Health sector staff under the HiAP initiative. In terms of ideas, there was wide acceptance of the role of social determinants in shaping health and the importance of action to promote health in all government agencies. The institutional environment was initially supportive, but support waned over the course of the study when the economy in South Australia became less buoyant and a health minister less supportive of health promotion took office. The existence of a HiAP Unit was very helpful for gaining support from other sectors. A new Public Health Act offered some promise of institutionalising the HiAP approach and ideas. The analysis concludes that a key factor was the operation of a supportive network of public servants who promoted HiAP, including some who were senior and influential. The South Australian case study demonstrates that despite institutional constraints and shifting political support within the health sector, HiAP gained traction in other sectors. The key factors that encouraged the commitment of others sectors to HiAP were the existence of a supportive, knowledgeable policy network, political support, institutionalisation of the ideas and approach, and balancing of the economic and social goals of government.


Symptomatic intravertebral disc herniation (Schmorl's node) in the cervical spine.
A case of a Schmorl's node in the cervical vertebra causing neck pain is reported. An inflammatory focus was found on histological examination of Schmorl's node indicating a possible mechanism of pain production.


Synergistic effects of a novel nanoporous stent coating and tacrolimus on intima proliferation in rabbits.
To overcome the problem of in-stent restenosis, the concept of local delivery of antiproliferative or immunosuppressive drugs has been introduced into interventional cardiology. Local drug delivery can be achieved by drug-eluting stents coated with polymer surfaces used for controlled drug release. However, several polymer coatings have shown an induction of inflammatory response and increased neointima formation. In the present study, the effect of a new inorganic ceramic nanoporous aluminum oxide (Al(2)O(3)) coating on neointima proliferation and its suitability as a carrier for the immunosuppressive drug tacrolimus have been investigated. 316 L stainless steel coronary stents were coated with a 500 nm thin nanoporous aluminum oxide layer. This ceramic nanolayer was used as a carrier for tacrolimus. Bare stents (n = 6), ceramic coated stents (n = 6), and ceramic coated stents loaded with 60 (n = 7) and 120 mug (n = 6) tacrolimus were implanted in the common carotid artery of New Zealand rabbits. The ceramic coating caused no significant reduction of neointimal thickness after 28 days. Loading the ceramic stents with tacrolimus led to a significant reduction of neointima thickness by 52% for 60 mug (P = 0.047) and 56% for 120 mug (P = 0.036) as compared to the bare stents. The ceramic coating alone as well as in combination with tacrolimus led to a reduced infiltration of lymphocytes and macrophages in the intima in response to stent implantation. Ceramic coating of coronary stents with a nanoporous layer of aluminum oxide in combination with tacrolimus resulted in a significant reduction in neointima formation and inflammatory response. The synergistic effects of the ceramic coating and tacrolimus suggest that this new approach may have a high potential to translate into clinical benefit.


BMP-treated human embryonic stem cells transcriptionally resemble amnion cells in the monkey embryo.
Human embryonic stem cells (hESCs) possess an immense potential to generate clinically relevant cell types and unveil mechanisms underlying early human development. However, using hESCs for discovery or translation requires accurately identifying differentiated cell types through comparison with their in vivo counterparts. Here, we set out to determine the identity of much debated BMP-treated hESCs by comparing their transcriptome to recently published single cell transcriptomic data from early human embryos ( Xiang et al., 2020). Our analyses reveal several discrepancies in the published human embryo dataset, including misclassification of putative amnion, intermediate and inner cell mass cells. These misclassifications primarily resulted from similarities in pseudogene expression, highlighting the need to carefully consider gene lists when making comparisons between cell types. In the absence of a relevant human dataset, we utilized the recently published single cell transcriptome of the early post implantation monkey embryo to discern the identity of BMP-treated hESCs. Our results suggest that BMP-treated hESCs are transcriptionally more similar to amnion cells than trophectoderm cells in the monkey embryo. Together with prior studies, this result indicates that hESCs possess a unique ability to form mature trophectoderm subtypes via an amnion-like transcriptional state. This article has an associated First Person interview with the first author of the paper.


Effect of glucose on renal excretion of electrolytes in the rat.
Glucose ingestion or infusion increases calcium and magnesium excretion in the human. To assess the role of renal tubular glucose reabsorption and of the parathyroid glands in this phenomenon, we performed standard two-phase clearance experiments in fed, volume-expanded male Sprague-Dawley rats. When compared with a group of animals receiving only 0.9% NaCl (group I), animals infused with glucose (group II) excreted significantly more calcium at any given level of sodium excretion (delta FECa, 1.95 +/- 0.24 vs. 0.69 +/- 0.18, P < 0.001). Normoglycemic hyperinsulinemia (group III) did not reproduce this increase in calcium excretion. In the group given phloridzin during sustained hyperglycemia (group IV), calcium excretion was well below that of control animals at any given level of sodium excretion. The glycosuric-hyperglycemia group (group V) used to assess the effect of glycosuria seen in group IV responded with a striking calciuria (delta FECa, 3.31 +/- 0.43, P < 0.001, compared with group IV). TPTX animals responded to glucose in the same way as intact animals (delta FECa, 4.8 +/- 0.5 vs. 2.18 +/- 0.3 in TPTX saline controls, P < 0.001). Magnesium excretion in all groups followed the same pattern as calcium. We conclude that renal tubular glucose reabsorption is essential for glucose to augment calcium and magnesium excretion. The presence of the parathyroid glands was not required for this phenomenon to occur.


Thermoelectric properties of double-substituted tetrahedrites Cu12-xCoxSb4-yTeyS13.
Tetrahedrites, a class of earth-abundant minerals, exhibit extremely low thermal conductivity values making them promising candidates for thermoelectric applications at high temperatures. Herein, we extend investigations on these materials to specimens substituted on both the Cu and Sb sites by reporting on the thermoelectric properties of polycrystalline Cu12-xCoxSb4-yTeyS13 in a wide range of temperatures (2-700 K). All prepared samples exhibit p-type heavily-doped semiconducting behavior with relatively low electrical resistivity values. These substitutions have little influence on the thermal conductivity, which remains very low in the whole temperature range (∼0.7 W m(-1) K(-1)). Although the double-substituted samples exhibit higher ZT values with respect to the parent tetrahedrite Cu12Sb4S13, the maximum ZT of 0.80 reached at 700 K for (x,y) = (0.82, 0.41) remains comparable to the values obtained in compounds solely substituted with Co or Te.


Resistance training exercise and creatine in patients with Charcot-Marie-Tooth disease.
Resistance exercise and creatine supplementation independently improve strength and function in patients with certain neuromuscular diseases. The purpose of this study was to examine the effects of resistance training with and without creatine supplementation on muscle, strength, and function in patients with Charcot-Marie-Tooth (CMT) disease. Twenty patients with CMT consumed 5 g/day creatine or placebo while participating in resistance training for 12 weeks. Energy metabolites, muscle fiber type and size, strength, and timed activities of daily living were measured before and after training. There were no differences between creatine or placebo groups for any outcome. For the groups combined, exercise training increased type I muscle fiber diameter (48.2 +/- 14.2 microm vs. 55.4 +/- 14.8 microm), strength, and activities of daily living (ADL) times. Thus, patients respond to resistance training with muscle fiber adaptations, and improvements in strength and function. Creatine was not beneficial.


Predicting road crashes from a mathematical model of alertness regulation--The Sleep/Wake Predictor.
Sleepiness is related to factors such as the time of day, the time since awakening and the duration of prior sleep. The present study investigated whether actual road crashes could be predicted from a mathematical model based on these three factors (the Sleep/Wake Predictor-SWP). Data were derived from a population-based case-control study of serious injury crashes. Data on accident time (or control sampling time) and start and end of prior sleep were entered into the model (blind). The predicted sleepiness values were used in logistic regressions. The results showed a highly significant odds ratio (OR)=1.72 (confidence interval=1.41-2.09) for each incremental step of sleepiness on the output sleepiness scale (nine steps). There was also a significant interaction with blood alcohol level, showing high OR values for high sleepiness levels and alcohol levels above 50 mg% (0.05 g/dl). It was concluded that the model is a good predictor of road crashes beyond that of alcohol level, and that interaction between the two carries a very high risk.


Non-corticosteroid treatment for nephrotic syndrome in children.
Eighty to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. About half relapse frequently and are at risk of the adverse effects of corticosteroids. Non-corticosteroid immunosuppressive agents are used to prolong periods of remission in these children, however these agents have significant potential adverse effects. Currently there is no consensus as to the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. To evaluate the benefits and harms of non-corticosteroid immunosuppressive agents in relapsing SSNS in children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists, conference abstracts and contact with known investigators. Search date: September 2007 Randomised controlled trials (RCTs) or quasi-RCTs were included if they compared non-corticosteroid agents with placebo, prednisone or no treatment, different doses and/or durations of the same non-corticosteroid agent, different non-corticosteroid agents. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). We identified 26 studies (1173 children). Cyclophosphamide (RR 0.44, 95% CI 0.26 to 0.73) and chlorambucil (RR 0.15, 95% CI 0.02 to 0.95) significantly reduced the relapse risk at six to twelve months compared with prednisone alone. There was no difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) and levamisole (RR 0.43, 95% CI 0.27 to 0.68) was more effective than steroids alone but the effects were not sustained once treatment was stopped. There was no difference in the risk for relapse between mycophenolate mofetil and cyclosporin (RR 5.00, 95% CI 0.68 to 36.66) but CI were large. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. Eight week courses of cyclophosphamide or chlorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Clinically important differences in efficacy are possible and further comparative studies are still needed.


Neuropsychiatry. An old discipline in a new gestalt bridging biological psychiatry, neuropsychology, and cognitive neurology.
The recent developments of psychiatry getting better insight into the biological basis of psychiatric disorders questions the old division between psychiatry and neurology. The present paper focus on the concept of neuropsychiatry, its historical antecedents and closely associated disciplines like biological psychiatry, behavioral neurology and neuropsychology. A special emphasis is put on the question of function and localization; the suggestions are made that the concept of neuronal integration may bridge the often discussed gap between localization and holism in the relation between function and brain regions. Examples of different mechanisms of neuronal integration are discussed and applied to specific neuropsychiatric disorders. It is concluded that the concept of neuronal integration may offer an appropriate conceptual tool to establish the concept of neuropsychiatry in a new and meaningful gestalt at the interface between biological psychiatry, neuropsychology and cognitive neurology.


Poly (ADP-ribose) polymerase (PARP): rationale, preclinical and clinical evidences of its inhibition as breast cancer treatment.
The chance to take advantage of genetic defects of cancer cells is a promising clinical tool in breast cancer therapy. Among the genetic aberrations, dysfunctions in DNA repair mechanisms are quite common and suitable for an attractive antitumor effect. Poly (ADP-ribose) polymerase I (PARP-1) is an enzyme with many functions in transcriptions and cell cycle regulation and in coordination of cellular response to DNA damage. Its involvement in tumorigenesis is witnessed by the overexpression found in different primary human tumors, where the increased enzymatic activity leads to cancer cell protection against DNA damage and instability. Therefore, activity of PARP and the opportunity to block it, mainly in cancer cells also deficient in other mechanisms of repair, are promising. In this review, areas covered include the main DNA repair mechanisms, the role of PARP enzymatic activity in diverse cell pathways as well as the preclinical and clinical data with PARP inhibitors. Despite the theoretical role of PARP inhibitors as therapeutic strategy in specific subtypes of breast cancer (hereditary BRCA1/BRCA2 mutation-related cancers and sporadic triple-negative breast cancer), questions are still open. More exhaustive knowledge is needed about other important functions of PARPs in cellular homeostasis and about escape mechanisms of cancer cells to inhibitory effect of PARP inhibitors.


Pearls and oy-sters: tuberculous meningitis: not a diagnosis of exclusion.
A 21-year-old man presented to his local emergency department with 5 days of headache, which was dull, occipital, bilateral, nonthrobbing, and progressively worsening. It was associated with mild fever, photophobia, and neck pain and stiffness. He had no history of headache, chronic illness, recent vaccinations, cutaneous rash, cough, diarrhea, arthralgia, or myalgia. He was from Ecuador and had been living in the United States for less than 1 year. He had been incarcerated while in Ecuador. Sublingual temperature on admission was 102.6°F. Other vital signs were within normal limits. On physical examination, he appeared thin but not cachectic. He had meningismus and photophobia, but no papilledema and his mental status was alert and attentive. There were no focal neurologic deficits. CSF contained red blood cells: 24 × 10(3)/μL; white blood cells: 85/μL (lymphocytic predominant); protein: 128 mg/dL; and glucose: 48 mg/dL (CSF/serum glucose ratio = 0.53). CSF Gram stain and cultures, PPD test, and blood and urine cultures were all negative. CT scan of the head on day of admission was entirely normal. MRI without gadolinium contrast showed a single punctate T2 hyperintensity in the left frontal periventricular white matter. Chest radiograph was clear. He received empiric vancomycin, ceftriaxone, and acyclovir. Corticosteroids were not given. The patient did not improve with antibiotics and continued to be intermittently febrile. On day 5, he became abruptly more somnolent, then comatose, opening eyes only to pain, his pupils were 5 mm and reactive, he had intact brainstem reflexes, withdrawing both arms and legs. Emergent head CT showed development of hydrocephalus and a ventriculoperitoneal shunt was emergently placed. The neurologic examination did not improve after shunt placement, and repeat head CT showed increased hydrocephalus with bilateral cerebral infarcts. On day 11, he was transferred to Columbia University Medical Center for intensive care. He was febrile and comatose. He did not open his eyes to pain, pupils were 7 mm minimally reactive, brainstem reflexes were intact, and he exhibited extensor posturing to pain. Mannitol was given, corticosteroid therapy was started, and an extraventricular drain was placed. The next day, his right pupil was 8 mm and nonreactive. MRI showed diffuse contrast enhancement of the arachnoid, extensive infarction of basal ganglia, midbrain, and pons, and small ring-enhancing lesions in the cerebellum (figure 1, A-D). Repeat lumbar puncture showed red blood cells: 550 × 10(3)/μL; white blood cells: 250/μL (14% neutrophils, 80% lymphocytes, 6% monocytes); protein: 65 mg/dL; and glucose: <10 mg/dL (CSF/serum glucose ratio = 0.08). CSF testing for Cryptococcus and toxoplasmosis was negative. CSF acid fast bacilli (AFB) smear was negative ×2, and CSF nucleic acid amplification test was also negative for tuberculosis. Serum HIV test was negative. Not until 14 days after initial presentation and 3 days after transfer to the intensive care unit was antituberculosis therapy finally started, because the pattern of infarcts on the MRI suggested basilar meningitis and he had not improved on broad-spectrum antibiotics. That same day, the first sputum AFB smear was positive, as were all succeeding daily sputum AFB smears. Tuberculosis nucleic acid amplification was positive from the sputum, but persistently negative from the CSF. Daily portable chest radiographs had been normal (read as likely atelectasis), but chest CT showed dense consolidations in the left lung and diffuse micronodular opacities throughout both lungs. Two days later, only 21 days after the onset of his headache, the patient died of cardiopulmonary arrest secondary to transtentorial cerebral herniation. Thirteen days later, the CSF culture became positive for Mycobacterium tuberculosis sensitive to streptomycin, isoniazid, ethambutol, rifampin, and pyrazinamide.


Should Artificial Intelligence Play a Role in Cultivating Social Connections Among Older Adults?
This article draws on 4 case studies from our group's research on older adults living alone in the United States and suggests how artificial intelligence (AI) applications can be used to foster meaningful social connections. This article also warns against ways in which AI applications can reduce physical connections and suggests how AI technology should be implemented to avoid this drawback.


Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities.
Endothelial dysfunction has been implicated as a key factor in the development of a wide range of cardiovascular diseases, but its definition and mechanisms vary greatly between different disease processes. This review combines evidence from cell-culture experiments, in vitro and in vivo animal models, and clinical studies to identify the variety of mechanisms involved in endothelial dysfunction in its broadest sense. Several prominent disease states, including hypertension, heart failure, and atherosclerosis, are used to illustrate the different manifestations of endothelial dysfunction and to establish its clinical implications in the context of the range of mechanisms involved in its development. The size of the literature relating to this subject precludes a comprehensive survey; this review aims to cover the key elements of endothelial dysfunction in cardiovascular disease and to highlight the importance of the process across many different conditions.


Lower garment-lifting postural control characteristics during toilet-related activities in healthy individuals and a post-stroke hemiplegic patient undergoing rehabilitation.
[Purpose] This study compared lower garment-lifting postural control characteristics during toilet-related activities between healthy participants and a post-stroke patient, and studied changes in the stroke patient's characteristics during rehabilitation. [Participants and Methods] Six healthy individuals and one stroke participant with right hemiparesis were asked to lift a pair of pants with the left arm while on the toilet. During the process, we measured the mean percentage of body weight (%BW) on each leg and the foot center of pressure (COP) using portable force plates. Measurements were conducted twice for the stroke participant during rehabilitation. [Results] In healthy participants, the %BW and respective COP indices for both legs were not different during lifting, but the COP sway velocity and excursion were greater in the anterior-posterior (AP) than the lateral axis in both legs. In the stroke participant, no marked change was seen in the high %BW of the non-paretic leg while lifting during rehabilitation, but both legs' COP positional asymmetry improved on the AP axis and the COP sway velocity and excursion of the non-paretic leg increased. [Conclusion] Facilitating selective COP mobility on the AP axis of the non-paretic leg during lower garment lifting could become an effective intervention for stroke patients.


Placement of markers to assist minimally invasive resection of peripheral lung lesions.
With development of lung cancer screening programs and increased utilization of radiographic imaging there is significantly higher detection of smaller lung nodules and subsolid lesions. These nodules could be malignant and pose a diagnostic challenge. Video-assisted thoracoscopic surgery and robotic-assisted thoracoscopic surgery (RATS) represent minimally invasive methods for tissue sampling. Intraoperative identification of these lesions maybe difficult, requiring marking prior to surgery. We review different techniques for the placement of markers to assist in the resection of peripheral lung lesions (PLL).


Intercontinental transport of air pollution: will emerging science lead to a new hemispheric treaty?
We examine the emergence of InterContinental Transport (ICT) of air pollution on the agendas of the air quality and climate communities and consider the potential for a new treaty on hemispheric air pollution. ICT is the flow of air pollutants from a source continent (e.g., North America) to a receptor continent (e.g., Europe). ICT of air pollutants occurs through two mechanisms: (i) episodic advection and (ii) increasing the global background, which enhances surface concentrations. We outline the current scientific evidence for ICT of aerosols and ozone, both of which contribute to air pollution and radiative forcing. The growing body of scientific evidence for ICT suggests that a hemispheric-scale treaty to reduce air pollutant concentrations may be appropriate to address climate and air quality concerns simultaneously. Such a treaty could pave the way for future climate agreements.


Chlamydia psittaci induced pneumonia in a horse.
An agent lethal to embryonated chicken eggs was isolated from lung tissues of a quarter horse mare with a fatal respiratory disease. The lesions induced in embryonated chicken eggs, the tinctoral properties, the ultrastructural morphology, the resistance of the organism to sodium sulfadiazine, and the presence of a chlamydial complement fixing antigen, identify this isolate as a member of the family Chlamydiaceae and suggest the agent to be Chlamydia psittaci. Two Shetland ponies experimentally infected with the isolated agent developed subclinical infection as demonstrated by an increase in complement fixing antibody titers. Post mortem examination of one pony revealed microscopic evidence of a generalized chlamydial infection. Lesions of interstitial pneumonia and focal hepatic necrosis were observed, and Chlamydia psittaci subsequently was reisolated from the lung tissues of the pony.


Thermoresponsive Elastin-b-Collagen-Like Peptide Bioconjugate Nanovesicles for Targeted Drug Delivery to Collagen-Containing Matrices.
Over the past few decades, (poly)peptide block copolymers have been widely employed in generating well-defined nanostructures as vehicles for targeted drug delivery applications. We previously reported the assembly of thermoresponsive nanoscale vesicles from an elastin-b-collagen-like peptide (ELP-CLP). The vesicles were observed to dissociate at elevated temperatures, despite the LCST-like behavior of the tethered ELP domain, which is suggested to be triggered by the unfolding of the CLP domain. Here, the potential of using the vesicles as drug delivery vehicles for targeting collagen-containing matrices is evaluated. The sustained release of an encapsulated model drug was achieved over a period of 3 weeks, following which complete release could be triggered via heating. The ELP-CLP vesicles show strong retention on a collagen substrate, presumably through collagen triple helix interactions. Cell viability and proliferation studies using fibroblasts and chondrocytes suggest that the vesicles are highly cytocompatible. Additionally, essentially no activation of a macrophage-like cell line is observed, suggesting that the vesicles do not initiate an inflammatory response. Endowed with thermally controlled delivery, the ability to bind collagen, and excellent cytocompatibility, these ELP-CLP nanovesicles are suggested to have significant potential in the controlled delivery of drugs to collagen-containing matrices and tissues.


[The dentist's role in the case of a suspected facial melanoma].
A 78-year-old patient was referred by her dentist to the Department of Oral and Maxillofacial Surgery because of a number of grey-blue lesions on the inferior alveolar ridge and a number of skin lesions in the face. One of the skin lesions proved to be a melanoma, which was treated with a substantial excision and sentinel node procedure. A complete anamnesis and of both intraoral and extra-oral investigation in the dental practice is very important.


Sequence and functional analysis of the envelope glycoproteins of hepatitis C virus variants selectively transmitted to a new host.
Hepatitis C virus (HCV) remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hypervariable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from nontransmitted variants in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetent host may thus be more complex than those suggested by mouse models. Human antibodies directed against HCV envelope effectively cross-neutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.


In vivo tracking of bioorthogonally labeled T-cells for predicting therapeutic efficacy of adoptive T-cell therapy.
Non-invasive tracking of T-cells may help to predict the patient responsiveness and therapeutic outcome. Herein, we developed bioorthogonal T-cell labeling and tracking strategy using bioorthogonal click chemistry. First, ovalbumin (OVA) antigen-specific cytotoxic T-cells (CTLs) were incubated with N-azidoacetyl-D-mannosamine-tetraacylated (Ac4ManNAz) for incorporating azide (N3) groups on the surface of CTLs via metabolic glycoengineering. Subsequently, azide groups on the CTLs were chemically labeled with near infrared fluorescence (NIRF) dye, Cy5.5, conjugated dibenzylcyclooctyne (DBCO-Cy5.5) via bioorthogonal click chemistry, resulting in Cy5.5-labeled CTLs (Cy5.5-CTLs). The labeling efficiency of Cy5.5-CTLs could be readily controlled by changing concentrations of Ac4ManNAz and DBCO-Cy5.5 in cultured cells. Importantly, Cy5.5-CTLs presented the strong NIRF signals in vitro and they showed no significant changes in the functional properties, such as cell viability, proliferation, and antigen-specific cytolytic activity. In ovalbumin (OVA)-expressing E.G-7 tumor-bearing immune-deficient mice, intravenously injected Cy5.5-CTLs were clearly observed at targeted solid tumors via non-invasive NIRF imaging. Moreover, tumor growth inhibition of E.G-7 tumors was closely correlated with the intensity of NIRF signals from Cy5.5-CTLs at tumors after 2-3 days post-injection. The Cy5.5-CTLs showed different therapeutic responses in E.G-7 tumor-bearing immune-competent mice, in which they were divided by their tumor growth efficacy as 'high therapeutic response (TR (+))' and 'low therapeutic response (TR (-))'. These different therapeutic responses of Cy5.5-CTLs were highly correlated with the NIRF signals of Cy5.5-CTLs at targeted tumor tissues in the early stage. Therefore, non-invasive tracking of T-cells can be able to predict and elicit therapeutic responses in the adoptive T-cell therapy.


Relationship of erythrocyte polyamine levels and growth rate of transplantable tumors in rats.
Varying levels of polyamines in the urine, plasma, and erythrocytes (RBC) of cancer patients have been demonstrated. The growth rate of the tumor has been suggested as a primary factor which determines whether the polyamine levels in urine are elevated. To further evaluate tumor size and growth rate as variables affecting polyamine levels in physiological fluids, the effect of a transplantable fibrosarcoma and colon tumor on the RBC polyamine levels of Fischer 344 rats was determined. The tumors were implanted s.c. and grew without metastasis or spontaneous regression. The fibrosarcoma grew exponentially up to a weight of approximately 69 +/- 15 (SD) g and was associated with a linear increase in RBC polyamine levels compared with that of non-tumor-bearing rats. RBC putrescine, spermidine, and spermine levels were significantly elevated at tumor weights of 12.5 +/- 1.4, 20.4 +/- 3.8, and 33.2 +/- 5.0 g, respectively. The respective polyamines increased consistently thereafter until the tumor weight was 57.8 +/- 5.8 g. In contrast with the fibrosarcoma, the colon tumor grew exponentially only to a weight of 9.2 +/- 4.7 g, at which time the growth rate of the tumor began to decrease (time T of the Gompertz model). RBC polyamine levels of rats with the colon tumor showed only a transient increase. RBC putrescine levels were significantly increased at a tumor weight of 12.9 +/- 1.2 g and spermidine at a tumor weight of 17.4 +/- 0.2 g. RBC spermine levels were significantly elevated at both tumor weights; thereafter, all RBC polyamine levels returned to normal. Host cachexia was evident when the fibrosarcoma and colon tumors weighed 12.5 +/- 0.9 and 7.2 +/- 2.6 g, respectively. The polyamine levels of the fibrosarcoma differed significantly from that of the colon tumor. These levels, however, did not correlate with the exponential growth rates. The results suggest that the tumor is the major source of elevated RBC polyamines. The data also suggest that the tumors must be rapidly growing for the elevation in polyamines to occur. This may partly explain why patients with extensive neoplastic disease that may have surpassed time T in the Gompertz model do not manifest abnormal polyamine levels.


Identifying a reliable boredom induction.
None of the tasks used to induce boredom have undergone rigorous psychometric validation, which creates potential problems for operational equivalence, comparisons across studies, statistical power, and confounding results. This methodological concern was addressed by testing and comparing the effectiveness of six 5-min. computerized boredom inductions (peg turning, audio, video, signature matching, one-back, and an air traffic control task). The tasks were evaluated using standard criteria for emotion inductions: intensity and discreteness. Intensity, the amount of boredom elicited, was measured using a subset of the Multidimensional State Boredom Scale. Discreteness, the extent to which the task elicited boredom and did not elicit other emotions, was measured using a modification of the Differential Emotion Scale. In both a laboratory setting (Study 1; N = 241) and an online setting with Amazon Mechanical Turk workers (Study 2; N = 416), participants were randomly assigned to one of seven tasks (six boredom tasks or a comparison task, a clip from Planet Earth) before rating their boredom using the MSBS and other emotions using the modified DES. In both studies, each task had significantly higher intensity and discreteness than the comparison task, with moderate to large effect sizes. The peg-turning task outperformed the other tasks in both intensity and discreteness, making it the recommended induction. Identification of reliable and valid boredom inductions and systematic comparison of their relative results should help advance state boredom research.


Use of a distal trochanteric osteotomy in hip revision.
Revision of some Moore stems with a straight lateral shoulder where the stem has subsided distally and laterally may be difficult and can result in fracture of the greater trochanter. A trochanteric osteotomy that extends a long way down the lateral cortex of the femur facilitates this type of revision. A similar approach simplifies revision of proximally-fixed noncemented stems.


The combined effect of two aqueous extracts on the growth of Trichomonas vaginalis, in vitro.
In this study a trial was performed to determine the effect of a combination of two aqueous extracts of two medicinal plants namely the violet, Viola odorata, and the rue, Ruta graveolens, with concentrations of 0.15625, 0.3125, 10-20 mg/cm3 on the growth of Trichomonas vaginalis cultured in (CM161) medium during periods of 24, 48, 72, and 96 hrs. The results showed that there is a variation of inhibition. Complete inhibition was seen with a concentration 10 mg/cm3 for 48 hrs. During the 96 hr. Period, 81% inhibition was achieved at a concentration of 0.3125mg /cm3 , and 75% at a concentration of 0.15625mg/cm3. A variety of interaction was observed in combination of violet and rue. Significant synergism was achieved at a concentration of 20 mg/cm3, and a suggestive synergism was achieved with 10 mg /cm3 In addition, partial antagonism occurred at a concentration of 0.15625mg /cm3 and an antagonism at 0.3125mg /cm3 was achieved.


Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors.
Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues.


Self-assembly of dinitrosyl iron units into imidazolate-edge-bridged molecular squares: characterization including Mössbauer spectroscopy.
Imidazolate-containing {Fe(NO)(2)}(9) molecular squares have been synthesized by oxidative CO displacement from the reduced Fe(CO)(2)(NO)(2) precursor. The structures of complex 1 [(imidazole)Fe(NO)(2)](4), (Ford, Li, et al.; Chem. Commun.2005, 477-479), 2 [(2-isopropylimidazole)Fe(NO)(2)](4), and 3 [(benzimidazole)Fe(NO)(2)](4), as determined by X-ray diffraction analysis, find precise square planes of irons with imidazolates bridging the edges and nitrosyl ligands capping the irons at the corners. The orientation of the imidazolate ligands in each of the complexes results in variations of the overall structures, and molecular recognition features in the available cavities of 1 and 3. Computational studies show multiple low energy structural isomers and confirm that the isomers found in the crystallographic structures arise from intermolecular interactions. EPR and IR spectroscopic studies and electrochemical results suggest that the tetramers remain intact in solution in the presence of weakly coordinating (THF) and noncoordinating (CH(2)Cl(2)) solvents. Mössbauer spectroscopic data for a set of reference dinitrosyl iron complexes, reduced {Fe(NO)(2)}(10) compounds A ((NHC-iPr)(2)Fe(NO)(2)), and C ((NHC-iPr)(CO)Fe(NO)(2)), and oxidized {Fe(NO)(2)}(9) compounds B ([(NHC-iPr)(2)Fe(NO)(2)][BF(4)]), and D ((NHC-iPr)(SPh)Fe(NO)(2)) (NHC-iPr = 1,3-diisopropylimidazol-2-ylidene) demonstrate distinct differences of the isomer shifts and quadrupole splittings between the oxidized and reduced forms. The reduced compounds have smaller positive isomer shifts as compared to the oxidized compounds ascribed to the greater π-backbonding to the NO ligands. Mössbauer data for the tetrameric complexes 1-3 demonstrate larger isomer shifts, most comparable to compound D; all four complexes contain cationic {Fe(NO)(2)}(9) units bound to one anionic ligand and one neutral ligand. At room temperature, the paramagnetic, S = (1)/(2) per iron, centers are not coupled.


Pubovaginal sling with a low-cost polypropylene mesh.
The aim of this study was to present the results of pubovaginal sling with a low-cost polypropylene mesh in the treatment of stress urinary incontinence. 118 women diagnosed with stress urinary incontinence (SUI) due to urethral hypermobility or intrinsic sphincteric deficiency, treated with pubovaginal sling (PVS) with a low-cost polypropylene mesh confectioned by the surgeon, were analyzed. All patients had a basic evaluation that included a medical history, physical examination, stress tests and urodynamic investigation. The average follow up was of 42 months. Urethral hypermobility was observed in 67% of the cases. The process was carried out on an outpatient basis on 67 patients. Intra-operative complications included 4 vesical injuries, treated with catheterization for 3 days. There were 13 early complications, of which 8 were urinary retentions treated with vesical drainage for 1 to 3 weeks and 3 vaginal extrusions of the mesh treated with covering of the sections with mucous membrane. There was a need for 6 urethrolysis in patients who presented irritative and postoperative obstructive symptoms; 81.3% of the patients were considered cured, while 9.3% had significant improvement. Three initially unsuccessful cases required sling reconfiguration. All cases were eventually cured. The construction of a pubovaginal sling using a low-cost polypropylene mesh is a safe and effective technique for the relief of SUI. It should be considered an alternative, especially for patients in public health systems with low financial resources.


An overview of the nature, causes, and consequences of abusive family relationships. Toward differentiating maltreatment and violence.
Despite gaps in research, this review argues for distinguishing family maltreatment from family violence, a differentiation between minimal or moderate abuse and serious endangerment, physical injury, or sexual violation. Most acts now defined as violent or abusive are moderate, and stressful life circumstances contribute to their development. Research suggests that abuse may develop through multiple pathways. The consequences of abuse appear to be general, but more commonalities may be found by examining more subtle and complex effects. Many interventions have attempted to prevent or treat family violence and its consequences, and several show promise. More systematic research is needed, but several changes in intervention seem warranted now. For instance, (a) mental health professionals should not be required to report maltreatment while a family is engaged in therapy; (b) the social service system needs to rediscover its roots in supporting families under stress, including in cases of moderate maltreatment; and (c) swift and decisive legal intervention is needed in cases of serious family violence.


[Stevens-Johnson syndrome and toxic epidermal necrolysis--updates and innovations].
Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions, usually induced by drugs. The reactions, which are characterized by extensive necrosis and detachment of the epidermis, followed by erosions of the skin and mucous membranes, are associated with high rates of mortality. There is growing evidence that SJS and TEN are a single disease with common causes and mechanisms. The present article summarizes recent updates and innovations related to the etiology, pathogenesis, genetic background, prognosis and treatment of these reactions. Among high-risk drugs associated with SJS/TEN, allopurinol is the most common cause of SJS/TEN in Europe and Israel. The prognosis of SJS/TEN can be predicted by a scoring system based on seven clinical and laboratory parameters. Founded on the genetic background of SJS/TEN, predictive tests can be used prior to starting high-risk medications. Treatment is still controversial, and further controlled studies are necessary.


Postmicrosomal protein fractions from short-time-predegenerated rat sciatic nerve.
The postmicrosomal protein fraction obtained from distal stumps of rat sciatic nerves at 0-6 days following transection were investigated by means of one- and two-dimensional electrophoresis. In all experimental groups, total amount of protein was significantly higher than in the control group. Proteins were resolved into 27 bands after SDS-PAGE. Their molecular weights ranged between 16.2 and 335.4 kDa. Eleven fractions displayed significant quantitative differences. After 2-D-electrophoresis, the pI of the proteins ranged from 4.2 to 7.4. They were resolved to 28 molecular masses from 13.5 kDa to 335.4 kDa. The greatest numbers of fractions (90-109) were observed on the 3rd, 4th, 5th and 6th day after nerve transection. Thus, during first 6 days after transection intensive changes in protein fraction content and composition take place in the distal stump of peripheral nerve. These processes seem to be most prominent on the 4th day after lesion. Results confirm our earlier in vivo findings.


Defect-Induced Secondary Crystals Drive Two-Dimensional to Three-Dimensional Morphological Evolution in the Co-Self-Assembly of Polyferrocenylsilane Block Copolymer and Homopolymer.
Bottom-up fabrication protocols for uniform 3D hierarchical structures in solution are rare. We report two different approaches to fabricate uniform 3D spherulites and their precursors using mixtures of poly(ferrocenyldimethylsilane) (PFS) block copolymer (BCP) and PFS homopolymer (HP). Both protocols are designed to promote defects in 2D assemblies that serve as intermediate structures. In a multistep seeded growth protocol, we add the BCP/HP mixture to (1D) rod-like PFS micelles in a selective solvent as first-generation seeds. This leads to 2D platelet structures. If this step is conducted at a high supersaturation, secondary crystals form on the basal surface of these platelets. Co-crystallization and rapid crystallization of BCP/HP promote the formation of defects that act as nucleation sites for secondary crystals, resulting in multilayer platelets. This is the key step. The multilayer platelets serve as second-generation seeds upon subsequent addition of BCP/HP blends and, with increasing supersaturation, lead to the sequential formation of uniform (3D) hedrites, sheaves, and spherulites. Similar structures can also be obtained by a simple one-pot direct self-assembly (heating-cooling-aging) protocol of PFS BCP/HP blends. In this case, for a carefully chosen but narrow temperature range, PFS HPs nucleate formation of uniform structures, and the annealing temperature regulates the supersaturation level. In both protocols, the competitive crystallization kinetics of HP/BCP affects the morphology. Both protocols exhibit broad generality. We believe the morphological transformation from 2D to 3D structures, regulated by defect formation, co-crystallization, and supersaturation levels, could apply to various semicrystalline polymers. Moreover, the 3D structures are sufficiently robust to serve as recoverable carriers for nanoparticle catalysts, exhibiting valuable catalytic activity and opening new possibilities for applications requiring exquisite 3D structures.


An economic review of compliance with medication therapy in the treatment of schizophrenia.
The authors examined published economic evaluations of schizophrenia and antipsychotic therapies to determine the role of compliance with medication therapy in the economic cost of schizophrenia. The authors reviewed studies published from 1995 to 2002 that evaluated compliance with treatment for schizophrenia. Literature searches were conducted for that period by using MEDLINE, EMBASE, and Current Contents. The primary search terms were "schizophrenia," "compliance," "relapse," and "economic costs." A definitive relationship exists between compliance and the economic costs of schizophrenia. Lower rates of compliance lead to higher costs of treating schizophrenia. However, the full implications are difficult to surmise from the literature because of inadequacies in the reporting of compliance rates and outcomes of treatment over time. The authors suggest collection of data on longer-term clinical outcomes as a means to improve future economic evaluations of schizophrenia treatments.


The classic basic protein of myelin--conserved structural motifs and the dynamic molecular barcode involved in membrane adhesion and protein-protein interactions.
The myelin basic protein (MBP) family comprises a variety of developmentally-regulated members arising from different transcription start sites, differential splicing, and post-translational modifications. The "classic" isoforms of MBP include the 18.5 kDa form, which predominates in adult human myelin and facilitates compaction of the mature myelin sheath in the central nervous system, thereby maintaining its structural integrity. In addition to membrane-association, the 18.5 kDa and all other classic isoforms are able to interact with a multitude of proteins, including Ca(2+)-calmodulin, actin, tubulin, and SH3-domain containing proteins, and thus may be signalling linkers during myelin development and remodelling. All proteins in this family are intrinsically disordered, creating a large effective surface to facilitate multiple protein associations, and are post-translationally modified to various degrees by methylation, phosphorylation, and deimination. We have used spectroscopic (fluorescence, CD, EPR, and NMR) approaches to study MBP's conformational adaptability. A highly-conserved central domain presents an amphipathic alpha-helix in association with a phospholipid membrane, and contains a threonyl residue that is phosphorylated by MAP-kinases. In multiple sclerosis, this segment represents a primary immunodominant epitope. This helical structure is adjacent to a proline-rich region that presents a classic SH3-ligand, comprises a second MAP-kinase phosphorylation site, and forms a polyproline type II helix. This domain of the protein is thus essential to proper positioning of a protein-interaction motif, with the local conformation and accessibility being modulated by MAP-kinases. In addition, the C-terminus of 18.5 kDa MBP has been identified by NMR spectroscopy as a Ca(2+)-calmodulin-binding site, and is of note for having a high density of post-translational modifications (protein kinase C phosphorylation, and deimination). For the most part, any classic protein isoform functions as an entropic spring that interacts in its entirety with membranes and cytoskeletal proteins, but the central and C-terminal motifs may represent molecular switches.


A Cluster of Fatal Tick-borne Encephalitis Virus Infection in Organ Transplant Setting.
Tick-borne encephalitis virus (TBEV) infection has become a major health problem in Europe and is currently a common cause of viral brain infection in many countries. Encephalitis in transplant recipients, althrough rare, is becoming a recognized complication. Our study provides the first description of transmission of TBEV through transplantation of solid organs. Three patients who received solid organ transplants from a single donor (2 received kidney, and 1 received liver) developed encephalitis 17-49 days after transplantation and subsequently died. Blood and autopsy tissue samples were tested by next-generation sequencing (NGS) and reverse transcription polymerase chain reaction (RT-PCR). All 3 recipients were first analyzed in autopsy brain tissue samples and/or cerebrospinal fluid by NGS, which yielded 24-52 million sequences per sample and 9-988 matched TBEV sequences in each patient. The presence of TBEV was confirmed by RT-PCR in all recipients and in the donor, and direct sequencing of amplification products corroborated the presence of the same viral strain. We demonstrated transmission of TBEV by transplantation of solid organs. In such a setting, TBEV infection may be fatal, probably due to pharmacological immunosuppression. Organ donors should be screened for TBEV when coming from or visiting endemic areas.


Undifferentiated sarcoma of the parotid gland with osseous metaplasia.
Malignant spindle cell tumors of the parotid gland are a diagnostic challenge. We present an unusual case of such a tumor that occurred in the right parotid gland of a 53-year-old man. The clinical and histologic assessments were consistent with a primary sarcoma of the parotid gland. The tumor was composed of sheets of pleomorphic, spindle-shaped cells with an area of bone formation. By immunohistochemistry, the tumor cells were positive for vimentin and negative for epithelial markers. Electron microscopy revealed mesenchymal cells containing moderate amounts of rough endoplasmic reticulum. The major differential diagnostic considerations were spindle cell carcinoma, carcinosarcoma, and primary undifferentiated sarcoma with osseous metaplasia. The lack of epithelial features and the benign appearance of the bone formation led to a diagnosis of undifferentiated sarcoma of the parotid gland.


The co-occurrence of Chiari type 1 malformation with syringomyelia and total situs inversus.
Total situs inversus (TSI) is a rare congenital anomaly that often occurs concomitantly with other disorders. TSI is the complete left-to-right inversion of the thoracic and abdominal organs. It develops due to an abnormal rotation of the cardiac tube during embryogenesis, the mechanism of which is of unknown mechanism. Syringomyelia (SM) is an uncommon disease of the spinal cord and is known as the occurrence of a cystic space in the middle of the spinal cord. SM occurs due to spinal cord injury, a primary tumor of the spinal cord, or an extramedullary lesion at the foramen magnum such as a Chiari type 1 malformation (CM1). In the literature there has been reported association of CM1 and SM (CM1/SM) with known genetic syndromes. We report a 33-year-old female with CM1/SM coexisting with TSI. Our patient presented with pain in the neck, arm, and upper back. She had no trauma history. There was dysesthesia in the cervical-2 dermatomes. Radiological tools revealed that CM1/SM with TSI accompanied by no other abnormality. It can be suggested that the existence of this case indicates that genetic factors may influence the pathogenesis of some CM1/SM cases.


Surgery-associated factor VIII inhibitors in patients without hemophilia.
The acquisition of antibodies to factor VIII (ie, factor VIII protein) by patients without hemophilia is associated with conditions such as pregnancy, lymphoma, and autoimmune disorders. We present three patients who acquired factor VIII antibodies in the postoperative setting. Preoperatively, none gave a history of bleeding even with past surgeries and all had normal coagulation tests. Within days of surgery (bowel resection, cholecystectomy, coronary bypass), a bleeding diathesis emerged with prolonged partial thromboplastin time, decreased factor VIII levels, and demonstrable factor VIII antibodies. All patients required multiple blood transfusions and urgent reexploration for hemostatic control. All were treated with high dose human factor VIII infusions, corticosteroids, and various forms of immunosuppression. We wish to raise awareness of surgery as a precipitating cause of acquired hemophilia, which is something to be considered with unusual postoperative bleeding. This syndrome is remarkable for its abrupt onset within days of surgery, dramatic bleeding, subsequent persistence, but potential reversal by immunosuppression.


Sensitive boundary condition dependence of noise-sustained structure.
Sensitive boundary condition dependence (BCD) is reported in a convectively unstable system with noise, where the amplitude of generated oscillatory dynamics in the downstream depends sensitively on the boundary value. This BCD is explained in terms of the decrease (relaxation) of the comoving Lyapunov exponent (characterizing the convective instability) from upstream to downstream [K. Fujimoto and K. Kaneko, Physica D 129, 203 (1999)]. It is shown that a fractal BCD appears if the dynamics that represent the spatial change of the fixed point includes transient chaotic dynamics, and if appropriate intensity of noise is presented. By considering as an example a one-way-coupled map lattice, this theory for BCD is demonstrated.


Chloramphenicol acetylation in Streptomyces.
Twenty-one strains of actinomycetes were screened for the presence of chloramphenicol acetyltransferase, the enzyme responsible for chloramphenicol resistance in many species of bacteria. Only five strains, belonging to three species, yielded mycelial lysates which catalysed the formation of chloramphenicol acetates in the presence of acetyl-coenzyme A: Streptomyces coelicolor Müller, S. acrimycini, and S. griseus. A mutant of S. acrimycini selected for an increase in resistance to chloramphenicol had a higher specific activity for chloramphenicol acetyltransferase than that found in the parental strain; the enzyme was not inducible in the mutant, the parental strain, or any other strain tested. Chloramphenicol was not acetylated by lysates of a strain of S. venezuelae, the organism known to produce it.


A modified formula for defining tissue phantom ratio of photon beams.
Tissue phantom ratio (TPR), for square fields of various dimensions has been determined at varying depths in water. The dose in water has been measured at a fixed source-to-surface distance (SSD) of 100 cm and reference depth of 5 cm for 6 MV photon beam of Siemens Linear Accelerator Primus 11 in German Cancer Research Center (DKFZ), Heidelberg, Germany. A modified formula has been developed to calculate the TPR value for isocentric treatment. The present article describes the conversion of the measured data values into a comprehensive and consistent data set by the modified formula, that gives the TPR from Percentage Depth Dose (PDD) with depth as a function of field sizes from 10 mm x 10 mm upto 300 mm x 300 mm) and depth (from 0 mm to 300 mm).


Substituent Effects That Control Conjugated Oligomer Conformation through Non-covalent Interactions.
Although understanding the conformations and arrangements of conjugated materials as solids is key to their prospective applications, predictive power over these structural factors remains elusive. In this work, substituent effects tune non-covalent interactions between side-chain fluorinated benzyl esters and main-chain terminal arenes, in turn controlling the conformations and interchromophore aggregation of three-ring phenylene-ethynylenes (PEs). Cofacial fluoroarene-arene (ArF-ArH) interactions cause twisting in the PE backbone, interrupting intramolecular conjugation as well as blocking chromophore aggregation, both of which prevent the typically observed bathochromic shift observed upon transitioning PEs from solution to solid. This work highlights two structural factors that determine whether the ArF-ArH interactions, and the resulting twisted, unaggregated chromophores, occur in these solids: (i) the electron-releasing characteristic of substituents on ArH, with more electron-releasing character favoring ArF-ArH interactions, and (ii) the fluorination pattern of the ArF ring, with 2,3,4,5,6-pentafluorophenyl favoring ArF-ArH interactions over 2,4,6-trifluorophenyl. These trends indicate that considerations of electrostatic complementarity, whether through a polar-π or substituent-substituent mechanism, can serve as an effective design principle in controlling the interaction strengths, and therefore the optoelectronic properties, of these molecules as solids.